PROBIOTICS: THE HOPE, THE HYPE, AND THE REALITY, SERIES #4

Jon A. Vanderhoof, M.D., Series Editor

Clinical Indications for Use of Probiotics in the Pediatric Population

Ryan S. Carvalho

Maria Oliva-Hemker

An increasing interest in health benefits achieved from the ingestion of live microorganisms has led to a dramatic expansion in the use of probiotics to treat or prevent human diseases. Clinical studies have reported beneficial effects of probiotics, primarily lactic acid producing bacteria, for infectious diarrhea, allergic diseases, irritable bowel syndrome, inflammatory bowel disease and necrotizing enterocolitis. This review will summarize recent clinical evidence on the use of probiotics in children with a focus on randomized controlled trials when available.

INTRODUCTION

lthough the use of live bacteria to promote health evolved from the work of Metchnikoff in 1908 it has only been recently that probiotics, defined as live microorganisms which when supplemented in adequate amounts confers a health benefit on the host have achieved widespread use (1,2). The most typical probiotic bacteria include those that are lactic acid

Ryan S. Carvalho, M.D. and Maria Oliva-Hemker, M.D., Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, MD.

producing such as Lactobacilli and Bifidobacter (Table 1). Currently, probiotics are being administered for health maintenance, immune enhancement and the prevention and treatment of a variety of medical conditions. The introduction of probiotics into food products has also helped spur a dramatic interest in this field by the lay population. However, the advertised health benefits of these products need to be viewed at this point with skepticism since probiotic dosages provided may be inadequate for therapeutic benefit and food processing may result in variable numbers of viable organisms compared to the commercially prepared probiotic formulations.
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Table 1 Microorganisms used as probiotics in clinical studies

Lactobacillus Species L. acidophilus L. casei ( rhamnosus) L. reuteri L. bulgaricus L. johnsonni L. lactis Bifidobacterium Species B. bifidum B. longum B. breve B. lactis B. infantis B. adolescentis
Other Species Bacillus cereus Escherichia coli Saccharomyces cervesisiae Saccharomyces boulardii Enterococcus fecalis Streptococcus thermophillus Propionibacterium freudenreichii ssp. shermanii JS

While the spectrum of indications for probiotics expands, their therapeutic use in children has also gained popularity. In this review we summarize the current indications for probiotic use as medical therapy in pediatric clinical practice. It is important to keep in mind that efficacy with one particular strain of probiotic does not imply that other strains will be equally efficacious, thus attention needs to be given to the organisms and preparations used in particular studies.

INFECTIOUS DIARRHEA
The most well documented probiotic studies involve the treatment and prevention of infectious diarrhea, particularly acute rotavirus diarrhea(3). Lactobacillus rhamnosus GG (LGG) and Lactobacillus reuteri have been shown to significantly reduce the severity and duration of acute viral enteritis in two trials enrolling well-nourished infants and children who
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presented with at least two days of diarrhea (4,5). In one of these trials, a multi-center European study, a decrease was observed in the duration of rotavirus diarrhea from 76.6 hours to 56.2 hours when patients were offered oral rehydrating solution plus LGG after initial rehydration (6). Other studies have shown a reduction in rotavirus shedding as well as an increased antibody response to rotavirus infection and rotavirus vaccine in children given LGG (79). The doses of probiotics used in these studies ranged from 1 to 10 billion colony forming units per gram (CFU/g). Three meta-analyses (Table 2) of existing clinical trials focusing on diarrhea in pediatric patients concluded that probiotic therapy shortens the duration of acute diarrhea in children by approximately 1 day (0.71.6 days) and decreases the number of stools with a beneficial effect starting at 3 days (7,8,10). Doses of 10 billion CFU/g appeared to be most efficacious suggesting that a certain threshold dose may be needed to achieve a therapeutic benefit. One meta-analysis demonstrated a significant linear association between the log of Lactobacillus dose and reduction in diarrhea duration in 8 of the studies reviewed (10). However, the authors of all three meta-analyses cautioned that no clear conclusion could be drawn regarding precise dose, duration of therapy and type of probiotic as different studies used different strains. While most studies dealing with infectious diarrhea have shown a therapeutic advantage a study done in children with moderate to severe diarrhea admitted to a metabolic facility in Brazil did not show a decrease in duration of diarrhea or stool frequency (11). The authors concluded that a lack of colonization by the probiotic due to the short duration of viral enteritis was the reason they failed to see any beneficial effects and concluded that probiotics would be most beneficial in children at high risk for developing prolonged diarrheal infections. While most controlled trials have focused on treatment of infectious diarrhea, a few have addressed diarrhea prevention (Table 3). These trials used B. lactis, S. thermophillus and LGG and demonstrated a decreased incidence and shorter duration of diarrheal illness concomitant with a decreased rate of viral shedding (1214). The studies were done in high risk populations of children where the burden of infectious diar(continued on page 55)

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(continued from page 52)
Table 2 Meta-analyses evaluating trials using probiotics to treat acute infectious diarrhea

Reference
Van Neil, 2001

No. of Trials Analyzed

9 (Pediatric)

Conclusions
Probiotics decrease duration of diarrhea by 0.7 days; probiotics reduce frequency of diarrhea by 1.6 stools on day 2 of treatment Probiotics decrease duration of diarrhea by approximately 1 day Probiotics decrease duration of diarrhea by 30.48 hours; probiotics reduce diarrhea risk at 3 days of treatment by 33%

Huang, 2002 Allen, 2004

18 (Pediatric) 23 (Adult and Pediatric)

Table 3 Randomized, controlled trials using probiotics for the prevention of acute infectious diarrhea

Reference
Chouraqui, 2004

Study Population
Infants <8 months

Probiotic Strain Bifidobacterium lactis strain Bb 12 (BbF).

Dose
1.5 108 CFU/L

Duration of Treatment Outcomes

137 days Lower risk of developing diarrhea; shorter episodes of diarrhea Decreased incidence of diarrhea in the 18 to 29 month age group at study end Decrease in events of diarrhea; decrease in rotaviral shedding

Oberhelman, 1999

Undernourished children (624 months)

Lactobacillus GG

3.7 1010 CFU/L

15 months

Saavedra, 1994

Infants (324 months)

Bifidobacterium lactis and Streptococcus thermophilus

1 108 CFU/g each

210 127 days

rhea was considered to be significant such as infants in a chronic medical care hospital and undernourished children in an underdeveloped country (12,14).

ANTIBIOTIC-ASSOCIATED DIARRHEA
Diarrhea occurs in approximately 20% of patients who receive antibiotics (15). Two randomized controlled trials have demonstrated that LGG reduces the risk of antibiotic-associated diarrhea in children (16,17). In the larger of the two trails, 188 children (ages 6 months10 years) receiving a 10 day course of antibiotics were given 1020 billion CFU/g of LGG per day (17). The group receiving LGG had an 18% decrease

in the incidence of diarrhea and a decrease in duration of diarrhea by 1.17 days compared to the placebo group. Randomized, placebo-controlled trials in adults using Saccharomyces boulardii and LGG have shown similar reductions in the incidence of antibiotic-associated diarrhea (18,19). Probiotics have also been used to prevent antibiotic associated diarrhea with antibacterial therapy for H. pylori infection (20). One meta-analysis of nine studies, which included the two pediatric trials mentioned above, has been published on probiotic use in antibiotic-associated diarrhea (21). The odds ratio in favor of active treatment over placebo in preventing diarrhea associated
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Table 4 Randomized controlled trials using probiotics for the treatment of allergic diseases

Reference
Viljanen, 2005

Study Population
230 infants (1.4 11.5 mos) with cow milk allergy

Probiotic Strain Lactobacillus GG or L. rhamnosus + Bifidobacter + P. freudenreichi L rhamnosus + L reuterii

Viable and heat inactivated Lactobacillus GG

Duration of Treatment
4 weeks

Outcomes LGG alleviated allergy symptoms in IgE-sensitized infants

Rosenfeldt, 2003 Kirjavainen, 2003

43 children (113 yrs) with atopic dermatitis 35 infants (3.56.8 mos) with cow milk allergy and eczema 27 infants (mean 4.6 mos) with atopic eczema

6 weeks

Decreased SCORAD*

7.5 weeks

Greatest decrease in SCORAD* in group treated with viable LGG SCORAD* decreased in the Bifidobacterium lactis Bb-12 and Lactobacillus GG groups

Isolauri, 2000

Bifidobacterium lactis Bb-12 or Lactobacillus strain GG

2 months

*SCORAD = SCORe of Atopic Dermatitis, a validated clinical scoring system for atopy with zero equaling no symptoms

with antibiotics was 0.39 (p < 0.001) for S. boulardii and 0.34 (p < 0.01) for Lactobacilli giving a combined odds ratio of 0.37 (p < 0.001) in favor of active treatment over placebo (22).

CLOSTRIDIUM DIFFICILE COLITIS

There are no published clinical trials for probiotic use in children at risk for developing recurrent C. difficile colitis. Two randomized controlled trials done in adults using LGG and Bifidobacter have shown a decrease in the rate of C. difficile toxin excretion in stools. (23, 24) In one of these trials, in patients with diarrhea the incidence of stool samples positive for C. difficile-associated toxins was 2.9% in the probiotic group compared with 7.2% in the placebo-control group (24).

treated group was 3.9% as compared to 7.5% in the placebo group (25). S. boulardii similarly showed a diminished incidence of diarrhea (28.7% versus 39.1% for placebo) in Austrian travelers but these results varied depending on the region of travel (26). No studies have been performed for this indication in children.

ALLERGIC DISEASES
In two landmark studies, Kalliomaki, et al demonstrated a decreased incidence of atopic eczema at 24 and 48 months in children who had been given LGG for six months after birth and whose mothers had received LGG during the last trimester of pregnancy (27, 28). In these studies, doses of probiotics exceeded one billion CFU/g. Another blinded, placebo-controlled trial randomized 230 infants to receive either LGG (ATCC 53103) or a mixture of 4 probiotics (LGG, L. rhamnosus LC705 (LC705), B. breve Bbi99 and Propionibacterium freudenreichii ssp. shermanii JS) or placebo. Only the LGG group was noted to significantly improve clinical symptoms in infants with
PRACTICAL GASTROENTEROLOGY OCTOBER 2005

TRAVELERS DIARRHEA
S. boulardii and LGG have been used in adult placebocontrolled trials for the prevention of travelers diarrhea (25,26). In 245 American travelers who received LGG for 13 weeks, the incidence of diarrhea in the

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IgE-associated atopic/eczema dermatitis syndrome, which highlights the importance of strain specific benefits (29). Other randomized controlled trials in pediatric patients have shown a benefit of LGG and B. lactis in the treatment and prevention of atopic eczema and dermatitis (Table 4). Clinical trials have also shown significant improvement in the course of atopic eczema in infants given probiotic-supplemented elimination diets. Isolauri, et al showed an improvement in the extent and severity of eczema in cows milk sensitive infants with atopic dermatitis who were given LGG (ATCC 53103), or B. lactis Bb12 in a hydrolyzed whey formula. A validated atopic dermatitis index score (SCORAD SCORe of Atopic Dermatitis) with a range of 0 (absence of signs and symptoms) to > 40 (severe symptoms) was used to measure outcome. With a mean starting score of 16 the SCORAD decreased in the B. lactis group to 0 (03.8), and in the LGG group to 1 (0.18.7) compared to 13.4 (4.518.2) in the unsupplemented group (30). The importance of probiotic viability was brought to light in a randomized, control trial which evaluated viable LGG or heat-inactivated LGG versus placebo in infants with atopic eczema and cows milk allergy. Heat-inactivated LGG was associated with adverse gastrointestinal symptoms leading to premature termination of study. However, the group of children receiving the viable-LGG demonstrated the greatest mean decrease in SCORAD score (19 to 5) compared with placebo (13 to 8) (31).

adjunct to standard therapy. A beneficial effect in reducing intestinal permeability and improving disease activity scores was demonstrated in an open labeled study in which 4 children with Crohns disease were given 1010 CFU of LGG twice daily for 6 months (33). Treatment of pouchitis has been the one area in IBD where the literature has provided the most convincing evidence for the use of probiotics (34,35). In a randomized controlled trial of adults with pouchitis in remission, 40 patients were randomized to receive 9 months of placebo or 600 billion viable lyophilized bacteria daily of the probiotic preparation VSL#3 (VSL Pharmaceuticals, Inc., Ft. Lauderdale, FL) which contained 4 strains of Lactobacillus (L. casei, L. plantarum, L. acidophilus, and L. delbrueckii subsp. bulgaricus), 3 strains of Bifidobacterium (B. longum, L. breve, and B. infantis), and 1 strain of Streptococcus (salivarius subsp. thermophilus). Eighty-five percent of those receiving VSL#3 were able to maintain remission compared to 0% of those receiving placebo during the study period. A subsequent study aimed at comparing VSL#3 to placebo in preventing onset of acute pouchitis during the first year after ileal pouchanal anastomosis showed that only 10% of patients treated with VSL#3 had an episode of acute pouchitis compared with 40% treated with placebo (P < 0.05) (35). VSL#3 has also been used to induce remission in adults with active ulcerative colitis (36).

IRRITABLE BOWEL SYNDROME (IBS)

In a short 4 week trial of adults randomized to receive preparations containing L. plantarum LP01 and B. breve BR03 or L. plantarum LP01 and L. acidophilus LA 02 in doses greater than 5 billion CFU/g per day there was a significant decrease in clinical pain and IBS symptom indices after 14 and 28 days with both probiotic preparations compared to placebo (37). Another double-blind, placebo-controlled trial, randomized adults to receive either Lactobacillus spp or Bifidobacterium spp for 8 weeks (38). Incorporating all symptoms, the researchers noted significant improvement in response to Bifidobacterium during all weeks of the study. Symptom and quality of life improvement was also greater with Bifidobacterium
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INFLAMMATORY BOWEL DISEASE (IBD)

In the only randomized, placebo-controlled trial using a probiotic in pediatric patients with Crohns disease, the effects on maintenance of clinical remission of LGG or placebo added to standard medical therapy was evaluated in a group of 75 children (32). In those receiving the probiotic, the median time to relapse of clinical symptoms was 9.8 months compared to 11.0 months in the placebo group (P = 0.24). Twelve of 30 (31%) children receiving LGG developed a relapse compared with 6/36 (17%) receiving placebo (P = 0.18). This study suggests that LGG does not prolong time to relapse in children with CD when given as an
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than with placebo or Lactobacillus. Similar to what has been noted in other trials, after the patients discontinued treatment, both symptoms and quality of life returned to baseline which highlights the necessity for continued ingestion of the probiotic to maintain a benefit (38). No studies have been performed in children with irritable bowel syndrome.

NECROTIZING ENTEROCOLITIS (NEC)

A multicenter Italian trial administering 6 billion CFU/g LGG daily to preterm infants for 47.3 26.0 days showed a trend towards the prevention of NEC as compared to a placebo treated group (39). Two subsequent randomized controlled trials have also shown a protective effect of probiotics in NEC (40, 41). In one, a Chinese study enrolling 367 very low birth weight infants, subjects were randomized to be fed breast milk with placebo or Infloran (Swiss Serum and Vaccine Institute, Berne, Switzerland) containing L. acidophilus and B. infantis at a dose of 125 mg/kg twice daily until hospital discharge (40,41). A significantly lower incidence of NEC was observed in the probiotic supplemented group (2 of 180) compared to the control group (10 of 187). No episodes of bacteremia or sepsis from the probiotic were noted in the treatment group. While the evidence in NEC prevention is promising, more standardized longitudinal studies are needed to establish therapeutic guidelines.

One clinical trial has used a probiotic as an adjunct to lactulose for the treatment of constipation in children. Eighty-four school children with constipation were randomized to receive 2 billion CFU/g LGG daily or placebo for 12 weeks. The primary treatment outcome measure, defined as passage of 3 or more spontaneous bowel movements per week, failed to show any difference between the treatment and placebo groups (43). Few studies have evaluated efficacy of probiotic supplementation (L reuterri, B lactis, S thermophillus and LGG) to reduce the rate of infections in day care centers. These only reaffirmed the role of probiotics in reducing the incidence of diarrhea but failed to show a decrease in respiratory infections, urinary tract infections and otitis media (12,39,44). Even beyond exploiting the natural capability of probiotics for therapeutic intervention, experimentation with probiotics genetically manipulated to deliver regulatory cytokines, replacement enzymes and pharmacologic agents has already begun and has the potential to revolutionize the use of probiotics (45).

CONCLUSION
In spite of the many questions that remain, and the larger clinical trials that need to be executed, the interest in therapeutic uses for probiotics in the pediatric population continues to increase. Of all the probiotic strains used, LGG has been the most frequently studied, however, the variability in doses, dosing frequency and strains used have made it difficult to develop general therapeutic guidelines. Nonetheless, given the ease of tolerance, excellent safety profile, and observed positive impact, probiotics appear to be reasonable therapeutic interventions in children for acute infectious diarrhea, antibiotic-associated diarrhea and atopic eczema/dermatitis syndrome.
References
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PRACTICAL GASTROENTEROLOGY OCTOBER 2005

OTHER INDICATIONS
The number of clinical conditions being treated with probiotics is on the rise. Some have yielded encouraging results, but overall, the data on all of these remains limited. One randomized, controlled trial has evaluated probiotic use in prevention of Helicobacter pylori infection (42). Three hundred twenty-six asymptomatic Chilean children from a low socioeconomic area diagnosed with H. pylori infection by a (13) C-urea breath test were randomized to receive placebo or either viable or heat-killed Lactobacillus johnsonii La1 or L. paracasei ST11 for 4 weeks. A moderate but significant difference in H. pylori colonization was detected in children receiving live L. johnsonii La1 and no differences were observed in the other groups.

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5. Isolauri E, Juntunen M, Rautanen T, et al. A human Lactobacillus strain (Lactobacillus casei sp strain GG) promotes recovery from acute diarrhea in children. Pediatrics, 1991; 88(1): 90-97. 6. Guandalini S, Pensabene L, Zikri MA, et al. Lactobacillus GG administered in oral rehydration solution to children with acute diarrhea: a multicenter European trial. J Pediatr Gastroenterol Nutr, 2000; 30(1): 54-60. 7. Huang JS, Bousvaros A, Lee JW, et al. Efficacy of probiotic use in acute diarrhea in children: a meta-analysis. Dig Dis Sci, 2002; 47(11): 2625-2634. 8. Allen SJ, Okoko B, Martinez E, et al. Probiotics for treating infectious diarrhoea. Cochrane Database Syst Rev, 2004(2): CD003048. 9. Szajewska H, Mrukowicz JZ. Probiotics in the treatment and prevention of acute infectious diarrhea in infants and children: a systematic review of published randomized, double-blind, placebocontrolled trials. J Pediatr Gastroenterol Nutr, 2001; 33 Suppl 2: S17-S25. 10. Van Niel CW, Feudtner C, Garrison MM, Christakis DA. Lactobacillus therapy for acute infectious diarrhea in children: a metaanalysis. Pediatrics, 2002; 109(4): 678-684. 11. Costa-Ribeiro H, Ribeiro TC, Mattos AP, et al. Limitations of probiotic therapy in acute, severe dehydrating diarrhea. J Pediatr Gastroenterol Nutr, 2003; 36(1): 112-115. 12. Saavedra JM, Bauman NA, Oung I, et al. Feeding of Bifidobacterium biidum and Streptococcus thermophillus to infants in hospital for prevention of diarrhea and shedding of rotavirus. Lancet, 1994; 344: 1046-1049. 13. Chouraqui JP, Van Egroo LD, Fichot MC. Acidified milk formula supplemented with Bifidobacterium lactis: impact on infant diarrhea in residential care settings. J Pediatr Gastroenterol Nutr, 2004; 38(3): 288-292. 14. Oberhelman RA, Gilman RH, Sheen P, et al. A placebo-controlled trial of Lactobacillus GG to prevent diarrhea in undernourished Peruvian children. J Pediatr, 1999; 134(1): 15-20. 15. Marteau P. Probiotics and intestinal health. Br J Nutr, 2002; 88: S51-S57. 16. Arvola T, Laiho K, Torkkeli S, et al. Prophylactic Lactobacillus GG reduces antibiotic-associated diarrhea in children with respiratory infections: a randomized study. Pediatrics, 1999; 104(5): e64. 17. Vanderhoof JA, Whitney DB, Antonson DL, et al. Lactobacillus GG in the prevention of antibiotic-associated diarrhea in children. J Pediatr, 1999; 135(5): 564-568. 18. Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospective study. Gastroenterology, 1989; 96(4): 981-988. 19. Siitonen S, Vapaatalo H, Salminen S, et al. Effect of Lactobacillus GG yoghurt in prevention of antibiotic associated diarrhoea. Ann Med, 1990; 22(1): 57-59. 20. Nista EC, Candelli M, Cremonini F, et al. Bacillus clausii therapy to reduce side-effects of anti-Helicobacter pylori treatment: randomized, double-blind, placebo controlled trial. Aliment Pharmacol Ther, 2004; 20(10): 1181-1188. 21. DSouza AL, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ, 2002; 324(7350): 1361. 22. DSouza AL Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ, 2002; 324: 1361. 23. Gorbach SL, Chang TW, Goldin B. Successful treatment of relapsing Clostridium difficle colitis with Lactobacillus GG. Lancet, 1987; 2(8574):1519. 24. Plummer S, Weaver MA, Harris JC, et al. Clostridium difficile pilot study: effects of probiotic supplementation on the incidence of C. difficle diarrhoea. Int Microbiol, 2004; 7(1): 59-62.

25. Hilton E, Kolakowski P, Singer C, Smith M. Efficacy of Lactobacillus GG as a Diarrheal Preventive in Travelers. J Travel Med, 1997; 4(1): 41-43. 26. Kollaritsch H, Holst H, Grobara P, Wiedermann G. Prevention of travelers diarrhea with Saccharomyces boulardii. Results of a placebo controlled double-blind study. Fortschr Med, 1993; 111(9): 152-156. 27. Kalliomaki M, Salminen S, Arvilommi H, et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet, 2001; 357(9262): 1076-1079. 28. Kalliomaki M, Salminen S, Poussa T, et al. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet, 2003; 361(9372): 1869-1871. 29. Viljanen M, Savilahti E, Haahtela T, et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a doubleblind placebo-controlled trial. Allergy, 2005; 60(4): 494-500. 30. Isolauri E, Arvola T, Sutas Y, et al. Probiotics in the management of atopic eczema. Clin Exp Allergy, 2000; 30(11): 1604-1610. 31. Kirjavainen PV, Salminen S, Isolauri E. Probiotic bacteria in the management of atopic disease: underscoring the importance of viability. J Pediatr Gastroenterol Nutr, 2003; 36:223227. 32. Bousvaros A, Guandalini S, Baldassano RN, et al. A randomized, double-blind trial of Lactobacillus GG versus placebo in addition to standard maintenance therapy for children with Crohns disease. Inflamm Bowel Dis, 2005; 11(9): 833-839. 33. Gupta P, Andrew H, Kirschner BS, Guandalini S. Is Lactobacillus GG helpful in children with Crohns disease? Results of a preliminary, open-label study. J Pediatr Gastroenterol Nutr, 2000; 31(4): 453-457. 34. Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology, 2000; 119(2): 305-309. 35. Gionchetti P, Rizzello F, Helwig U, et al. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology, 2003; 124(5): 1202-1209. 36. Bibiloni R, Fedorak RN, Tannock GW, et al. VSL#3 probioticmixture induces remission in patients with active ulcerative colitis. Am J Gastroenterol, 2005; 100(7): 1539-1546. 37. Saggioro A. Probiotics in the treatment of irritable bowel syndrome. J Clin Gastroenterol, 2004; 38(6 Suppl): S104-S106. 38. OMahony L, McCarthy J, Kelly P, et al. Lactobacillus and Bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology, 2005; 128(3): 541-551. 39. Dani C, Biadaioli R, Bertini G, et al. Probiotics feeding in prevention of urinary tract infection, bacterial sepsis and necrotizing enterocolitis in preterm infants. A prospective double-blind study. Biol Neonate, 2002; 82(2): 103-108. 40. Lin HC, Su BH, Chen AC, et al. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics, 2005; 115(1): 1-4. 41. Kliegman RM. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. J Pediatr, 2005; 146(5):A710. 42. Cruchet S, Obregon MC, Salazar G, et al. Effect of the ingestion of a dietary product containing Lactobacillus johnsonii La1 on Helicobacter pylori colonization in children. Nutrition, 2003; 19(9): 716-721. 43. Banaszkiewicz ASH. Ineffectiveness of Lactobacillus GG as an adjunct to lactulose for the treatment of constipation in children: a double-blind, placebo-controlled randomized trial. J Pediatr, 2005;146(3): 364-369. 44. Weizman Z, Asli G, Alsheikh A. Effect of a probiotic infant formula on infections in child care centers: comparison of two probiotic agents. Pediatrics, 2005; 115(1): 5-9. 45. Steidler L. Genetically engineered probiotics. Best Practise & Research, 2003; 17(5): 861-876.

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